This invention relates to substituted 2-(S)-hydroxy-3-(piperidin-4-yl-methylamino)-propyl ethers and substituted 2-aryl-2-(R)-hydroxy-1-(piperidin-4-yl-methyl)-ethylamine xcex23 adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and and frequent urination, and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of xcex2 adrenergic receptors (xcex2-AR) into xcex21- and xcex22-AR has led to the development of xcex21- and xcex22- antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of xe2x80x9catypicalxe2x80x9d receptors, later called xcex23-AR, has led to the development of xcex23-AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on xcex23-AR agnoists, see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.
Compounds that are potent and selective xcex23 agonists, may be potentially useful antiobesity agents. Low levels or lack of xcex21 and xcex22-agonistic properties will minimize or eliminate the adverse side effects that are associated with xcex21 and xcex22 agonistic activities, i.e. increased heart rate, and muscle tremor, respectively.
Early developments in the xcex23-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, 5,153,210. Although the early developments purport to claim compounds with greater xcex23-AR selectivity over the xcex21- and xcex22-AR. However, clinical trials in humans with those early developed xcex23-agonists have, so far, not been successful.
More recently, potent and selective human xcex23 agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures, expressing cloned human xcex23 receptors, which predict the effects that can be expected in humans (Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).
xcex23-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J H, Yasay G D and Kau S T Pharmacology 1992; 44: 13-18). Beta-adrenoceptor subtypes are in the detrusor of guinea-pig urinary bladder. Recently, a number of laboratories have provided experimental evidence of xcex23 adrenergic receptors in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Br. J. Pharmacol. 1998; 124: 593-599), and that activation of the xcex23 receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder.
Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized my abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, xcex23 adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled xcex23 receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the xcex23 adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, xcex23 adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective xcex23 adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
This invention provides compounds of Formula I having the structure 
wherein,
A is xe2x80x94OCH2xe2x80x94 or a bond;
R is
(a) aryl optionally substituted with R2, R3, R4, R5, or R6; or
(b) Het optionally substituted with R2, R3, or R4;
R1 is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) aryl optionally substituted with R9, R10, or R11;
(c) arylamino optionally substituted with R9, R10, or R11;
(d) arylalkyl having 1-6 carbon atoms in the alkyl moiety, and which the aryl moiety may be optionally substituted with R9, R10, or R11;
(e) Het optionally substituted with R9or R10 
R2, R3, R4, R5, and R6 are each, independently, alkyl of 1-6 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, halogen, xe2x80x94NHSO2R7, xe2x80x94CO2R8, or xe2x80x94CONH2;
R7 and R8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl moiety;
Z is a bond, xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94;
Het is
(a) a 5-6 membered heterocycle having 1-4 heteroatoms selected from O, N, and S;
(b) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring;
R9, R10, and R11 are each, independently:
(a) alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, trifluoromethylalkyl of 2-7 carbon atoms, trifluoromethoxy, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
(b) Het optionally substituted with R15; or 
R12 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted with R15, arylalkyl having 1-6 carbon atoms in the alkyl moiety and the aryl moiety optionally substituted with R15, Het optionally substituted with R15, Hetalkyl having 1-6 carbon atoms in the alkyl moiety and the Het moiety optionally substituted with R15, xe2x80x94(CH2)nxe2x80x94CO2R7, or xe2x80x94OCH2(CH2)nCO2R7;
R13 is alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R14 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R15 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
R16 is alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, xe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94CN, xe2x80x94NO2, or trifluoromethyl;
n=0-6;
with the proviso that when R is aryl, and R1 is Het, Z is not a bond;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human xcex23 adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
The compounds of the instant invention all contain at least one asymmetric center. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, are included within the scope of the instant invention. Any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of know configuration.
Alkyl and alkenyl include both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. Aryl includes monocyclic, bicyclic, or tricyclic aromatic carbocyclic groups such as phenyl, naphthyl, and fluorenyl. As defined in this invention, fluoren-9-one and fluoren-2-oxime are considered to be aryl moieties. Arylalkyl is defined as an aryl group bonded to a alkyl moiety. Benzyl is the preferred arylalkyl moiety. As used herein, a heterocyclic ring is a ring contining 1-4 heteroatoms selected from N, O, and S, indicates a heterocycle which may be saturated, unstaurated, or partially unsaturated. The heterocyclic ring may be attached within structural Formula I by any carbon atom or appropriate heteroatom. As described herein, the term heterocycle includes heterocyclic rings or ring systems in which ring carbon atoms may exist as a carbonyl group, or as an oxime of a carbonyl group. It is understood that the heterocyclic ring does not contain heteroatoms in arrangements which would make them inherently unstable. For example, the term heterocyclic ring does not include ring systems containing Oxe2x80x94O bonds in the ring backbone. Preferred heterocycles include pyridyl, piperidinyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benziodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridinyl, thienopyridinyl, thienyl, furyl, isoindolyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzofuranzanyl, carbazolyl, 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-indol-2-one, 1,2,3,4-tetrahydroquinolin-2-one, indazolyl, imidazolidin-2-one, and pyrazolyl, oxadiazolyl. More preferred heterocycles include carbazolyl, indolyl, 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-indol-2-one, 1,2,3,4-tetrahydroquinolin-2-one, quinolinyl, pyridyl, imidazolyl, thienyl, indazolyl, imidazolidin-2-one, pyrazolyl, oxadiazolyl, piperidyl, pyrrolidinyl, benzothiadiazolyl and pyrimidinyl.
Preferred compounds of Formula I are those in which
R is
(a) phenyl, naphthyl, fluorenyl, fluoren-2-one, or fluoren-2-oxime optionally substituted with R2, R3, R4, R5, or R6; or
(b) Het optionally substituted with R2, R3, or R4;
R1 is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) phenyl or naphthyl optionally substituted with R9, R10, or R11;
(c) phenylamino optionally substituted with R9, R10, or R11;
(d) benzyl in which the phenyl ring may be optionally substituted with R9, R10, or R11;
(e) Het optionally substituted with R9or R10 
Het is carbazolyl, indolyl, 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-indol-2-one, 1,2,3,4-tetrahydroquinolin-2-one, quinolinyl, pyridyl, imidazolyl, thienyl, indazolyl, imidazolidin-2-one, pyrazolyl, oxadiazolyl, piperidyl, pyrrolidinyl, benzothiadiazolyl or pyrimidinyl;
with the remaining subsitituent as defined above.
This invention also provides preferred compounds of Formula I, having the structure 
wherein,
A is xe2x80x94OCH2xe2x80x94 or a bond;
R is Het optionally substituted with R2, R3, or R4;
R1 is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) aryl optionally substituted with R9, R10, or R11;
(c) arylamino optionally substituted with R9, R10, or R11;
(d) arylalkyl having 1-6 carbon atoms in the alkyl moiety, and which the aryl moiety may be optionally substituted with R9, R10, or R11;
(e) Het optionally substituted with R9or R10 
R2, R3, R4, R5, and R6 are each, independently, alkyl of 1-6 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, halogen, xe2x80x94NHSO2R7, xe2x80x94CO2R8, or xe2x80x94CONH2;
R7 and R8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl moiety;
Z is a bond, xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94;
Het is
(a) a 5-6 membered heterocycle having 1-4 heteroatoms selected from O, N, and S;
(b) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring;
R9, R10, and R11 are each, independently:
(a) alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, trifluoromethylalkyl of 2-7 carbon atoms, trifluoromethoxy, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
(b) Het optionally substituted with R15; or 
R12 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted with R15, arylalkyl having 1-6 carbon atoms in the alkyl moiety and the aryl moiety optionally substituted with R15, Het optionally substituted with R15, Hetalkyl having 1-6 carbon atoms in the alkyl moiety and the Het moiety optionally substituted with R15, xe2x80x94(CH2)nxe2x80x94CO2R7, or xe2x80x94OCH2(CH2)nCO2R7;
R13 is alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R14 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R15 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
R16 is alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, xe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94CN, xe2x80x94NO2, or trifluoromethyl;
n=0-6;
or a pharmaceutically acceptable salt thereof.
This invention also provides preferred compounds of Formula I, having the structure 
wherein,
A is xe2x80x94OCH2xe2x80x94 or a bond;
R is
(a) aryl optionally substituted with R2, R3, R4, R5, or R6; or
(b) Het optionally substituted with R2, R3, or R4;
R1 is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) aryl optionally substituted with R9, R10, or R11;
(c) arylamino optionally substituted with R9, R10, or R11;
(d) arylalkyl having 1-6 carbon atoms in the alkyl moiety, and which the aryl moiety may be optionally substituted with R9, R10, or R11;
R2, R3, R4, R5, and R6 are each, independently, alkyl of 1-6 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, halogen, xe2x80x94NHSO2R7, xe2x80x94CO2R8, or xe2x80x94CONH2;
R7 and R8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl moiety;
Z is a bond, xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94;
Het is
(a) a 5-6 membered heterocycle having 1-4 heteroatoms selected from O, N, and S;
(b) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring;
R9, R10, and R11 are each, independently:
(a) alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, trifluoromethylalkyl of 2-7 carbon atoms, trifluoromethoxy, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
(b) Het optionally substituted with R15; or 
R12 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted with R15, arylalkyl having 1-6 carbon atoms in the alkyl moiety and the aryl moiety optionally substituted with R15, Het optionally substituted with R15, Hetalkyl having 1-6 carbon atoms in the alkyl moiety and the Het moiety optionally substituted with R15, xe2x80x94(CH2)nxe2x80x94CO2R7, or xe2x80x94OCH2(CH2)nCO2R7;
R13 is alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R14 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R15 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
R16 is alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, xe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94CN, xe2x80x94NO2, or trifluoromethyl;
n=0-6;
or a pharmaceutically acceptable salt thereof.
This invention also provides preferred compounds of Formula I, having the structure 
wherein,
A is xe2x80x94OCH2xe2x80x94 or a bond;
R is
(a) aryl optionally substituted with R2, R3, R4, R5, or R6; or
(b) Het optionally substituted with R2, R3, or R4;
R1 is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) aryl optionally substituted with R9, R10, or R11;
(c) arylamino optionally substituted with R9, R10, or R11;
(d) arylalkyl having 1-6 carbon atoms in the alkyl moiety, and which the aryl moiety may be optionally substituted with R9, R10, or R11;
(e) Het optionally substituted with R9 or R10 
R2, R3, R4, R5, and R6 are each, independently, alkyl of 1-6 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, halogen, xe2x80x94NHSO2R7, xe2x80x94CO2R8, or xe2x80x94CONH2;
R7 and R8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl moiety;
Z is xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94;
Het is
(a) a 5-6 membered heterocycle having 1-4 heteroatoms selected from O, N, and S;
(b) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring;
R9, R10, and R11 are each, independently:
(a) alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, trifluoromethylalkyl of 2-7 carbon atoms, trifluoromethoxy, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
(b) Het optionally substituted with R15; or 
R12 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted with R15, arylalkyl having 1-6 carbon atoms in the alkyl moiety and the aryl moiety optionally substituted with R15, Het optionally substituted with R15, Hetalkyl having 1-6 carbon atoms in the alkyl moiety and the Het moiety optionally substituted with R15, xe2x80x94(CH2)nxe2x80x94CO2R7, or xe2x80x94OCH2(CH2)nCO2R7;
R13 is alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R14 is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted by R16, or Het optionally substituted with R16;
R15 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, xe2x80x94(CH2)nxe2x80x94NHR14, xe2x80x94OCH2(CH2)nCO2R7, xe2x80x94(CH2)nxe2x80x94CO2R7, xe2x80x94COR7xe2x80x94SO2R13, xe2x80x94(CH2)nNHCOR14, xe2x80x94CN, or NO2;
R16 is alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, xe2x80x94CO2R7, xe2x80x94COR7, xe2x80x94CN, xe2x80x94NO2, or trifluoromethyl;
n=0-6;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
The compounds of formula I of the present invention where Z=OCH2 can be prepared by the regiospecific ring opening of a substituted (2S)-aryloxymethyl-oxirane of formula II 
wherein R is defined in relation to formula I
with an appropriately 1-substituted-4-(aminomethyl)-piperidine of formula III. 
where R1 is defined in relation to formula I and R15=H or trimethylsilyl.
When R15=H, ring opening of the chiral epoxide to give the xcex2-amino alcohol was carried out using conditions similar to those described by Klunder et al., JOC, (1989), 54, 1295. Thus, a mixture of 1 equivalent of the compounds of formula II and an excess of the compounds of formula III are heated as a solution in methanol at 60xc2x0 C. for 16-24 hours to provide, the chiral xcex2-amino alcohols of formula I.
For the case when R15=trimethylsilyl (TMS), the initially prepared free amine of formula II can be functionalized to the TMS analog as described in R. K. Atkins et al, Tet Lett, (1986), 27, 2451. The TMS analog can then be coupled with 1 equivalent of a compound of formula II as described above.
In the case of compounds of formula II where R=4-hydroxyphenyl, a mixture of 4-protected-oxy-phenoxymethyloxirane and an excess of the compounds of formula III are coupled to form intermediates of formula IV using the procedures stated above. 
wherein
P=benzyl or t-butyldiphenylsilyl.
When P=benzyl, deprotection to the phenol is accomplished by hydrogenation over 10% palladium on carbon using either hydrogen gas, or catalytic hydride transfer with cyclohexene or ammonium formate.
When P=tert-butyldiphenylsilyl, deprotection to the phenol is accomplished by treatment of the tert-butyidiphenylsilyl intermediates of formula IV with 1M tetrabutylammonium fluoride (TBAF) as described by Corey et al., JACS (1970), 94. 6190), in tetrahydrofuran (THF) to give compounds of formula I where R4=OH. The silyl protecting group may also be removed by treatment with hydrochloric acid as a solution in a solvent such as dioxane or by other suitable methods known to those skilled in the art.
Alternatively, compounds of formula I of the present invention can be prepared by reductive amination of substituted (2R)-hydroxyethylamines of formula V by the method of Borch, R F et al, JACS (1971), 93, 2897
wherein R is defined in relation to formula I
with appropriately (1-substituted-piperidin-4-ylmethyl)-carboxaldehydes of formula VI 
Thus, a solution of compounds of formula V and formula VI are stirred in the presence of 1 equivalent of acetic acid in a suitable solvent such as methanol to form the intermediate imine which is reduced to the substituted 2-aryl-2-(R)-hydroxy-1-(piperidin-4-yl-methyl)-ethylamine compounds of the present invention with a hydride source such as sodium cyanoborohydride.
Compounds of formula II can be conveniently prepared as outlined in Scheme 1. 
A mixture of a hydroxyaryl compound, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, and (S)-glycidyl nosylate is heated at reflux for at least 18 hours in an appropriate solvent such as 2-butanone (MEK) in the presence of a suitable base such as potassium carbonate to provide compounds of formula II.
Alternatively, compounds of formula II can be prepared from dropwise treatment of a solution of the hydroxyaryl compound, R(+)-glycidol and triphenylphosphine in dry THF with 1.1 eq. of diethylazodicarboxylate as described by O. Mitsinobu., Bull Soc. Chem Jap., (1967), 60, 2380.
Compounds of formula III can be conveniently prepared via Scheme 2. 
Thus, when R1=alkyl, hydroxyalkyl and Z=bond, reaction of commercially available isonipecotamide with an alkyl iodide (or bromide), either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in an appropriate solvent such as MEK and base such as potassium carbonate provides the intermediate carboxamides. The carbonyl can then be reduced conveniently to the desired 1-substituted-4-aminomethyl-piperidine with lithium aluminum hydride (LAH) in a solvent such as THF to give compounds of formula III.
The above procedure is also used for the case where R1=heteroaryl and Z=bond from reaction of isonipecotamide in an analogous fashion with chloro or bromo substituted heterocycles, either available commercially or are known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds.
Where R1 is defined in relation to formula I and Z=SO2, reaction of isonipecotamide with a substituted sulfonyl chloride, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in a solvent such as THF, dioxane or methylene chloride with an acid scavenger such as diisopropylethyl amine or other hindered organic base provides the intermediate 4-carboxamido-1-piperidinyl-substituted sulfonamides. Selective reduction of the amide carbonyl to the desired 4-aminomethyl-1-piperidinyl-substituted sulfonamides can be accomplished using a suitable reducing agent such as BH3-THF complex in THF to give compounds of formula III as described by Green et al., Tetrahedron (1995), 51, 2865.
Where R1 is defined in relation to formula I and Z=(Cxe2x95x90O), reaction of isonipecotamide with a substituted isocyanate, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in a solvent such as THF, dioxane, ethanol, methanol or methylene chloride provides the intermediate 1-(4-carboxamido-piperidin-1-yl)-3-substituted urea. Reduction of the amide carbonyl to the desired 1-(4-aminomethyl-piperidin-1-yl)-3-substituted urea can be accomplished using a suitable reducing agent such as BH3-THF complex in THF to give compounds of formula III.
Alternatively, the urea formation can be accomplished by first treating isonipecotamide with 0.33 equivalents of triphosgene dropwise over at least 1 hour in the presence of an acid scavenger such as diisopropylethyl amine. The other amine of choice is added in one portion to complete the urea formation.
Compounds of formula III may also be prepared from piperidin-4-ylmethyl-carbamic acid t-butyl ester as outlined in Scheme 3. 
Thus, in the case where R1 is defined in relation to formula I and Z=SO2, reaction of piperidin-4-ylmethyl-carbamic acid t-butyl ester with a substituted sulfonyl chloride, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in a solvent such as THF, dioxane or methylene chloride with an acid scavenger such as diisopropylethyl amine or other organic base. Several methods available for deprotection of the carbamate (Boc) are known (see Greene T., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley Interscience) to one skilled in the art. The preferred method used was treatment with neat formic acid or neat trifluoroacetic acid (TFA) to give sulfonamides of formula III.
Piperidin-4-ylmethyl-carbamic acid t-butyl ester is prepared as shown in Scheme 3 from reduction of 1-benzyl-isonipecotamide with LAH followed by Boc protection of the primary amine by treatment with di-t-butyidicarbonate in a suitable solvent such as dioxane-water in the presence of potassium carbonate.
Similarly compounds of formula VI where R1 is defined in relation to formula I and Z=SO2, may be prepared from 4-formylpiperidine dimethyl acetal as outlined in Scheme 4: 
Thus, reaction of 4-formylpiperidine dimethyl acetal with a substituted sulfonyl chloride, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in a solvent such as THF, dioxane or methylene chloride with an acid scavenger such as diisopropylethyl amine or other organic base followed by deprotection of the aldehyde with neat formic acid or neat TFA affords sulfonamides of formula VI. Deprotection may also be accomplished by treatment with trichloromethylsilane and sodium iodide in acetonitrile at ambient temperature using a procedure described by G. Olah et al, JOC (1983), 48, 3667.
4-Formylpiperidine dimethyl acetal is prepared as outlined in Scheme 4. Thus, 4-hydroxymethyl-1-piperidinyl carbamic acid benzyl ester is oxidized with pyridinium chlorochromate to the aldehyde which is protected as the dimethyl acetal by reaction with a large excess of trimethyl orthoformate in the presence of a catalytic amount of p-toluenesulfonic acid in a suitable solvent such as methanol.
Compounds of formula III and formula VI where Z=SO2, R1=analogs of the type 
and where R8 and R12 are defined in relation to formula I,
can be conveniently prepared from the intermediates of formula VIII. 
The intermediate of formula VIII, where R16 is the carboxamido derivative, can be converted to compounds of formula VII by reaction with reactive substituted isocyanates, either available commercially or are known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, to provide the urea. The carboxamide can be reduced with borane-THF as described above to the 1-[4-(4-aminomethyl-1-piperidinyl)-benzenesulfonyl]-3-substituted urea of formula VII.
The intermediate of formula VIII, where R16 is the Boc-aminomethyl moiety can be converted to ureas of formula VII by reaction of [1-(4-Aminobenzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester with 0.33 equivalents of triphosgene in the presence of an acid scavenger such as triethyl amine in an appropriate solvent such as THF or methylene chloride followed by a primary amine, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds. Alternatively a secondary amine can be used which is either available commercially, known in the art or can be prepared by procedures analogous to those in the literature for the known compounds. In the present invention these secondary amines are prepared by reaction of carboxylic acids activated by carbonyldiimidazole with primary amines described above in the presence of an organic base such as diisopropylethyl amine. Deprotection of the intermediate [1-(4-substituted ureido-benzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester is carried out with formic acid or TFA as described above to give compounds of formula VII.
Alternatively, [1-(4-Aminobenzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester can be derivatized to the urea by reaction with an isocyanate derived via Curtius rearrangement of an intermediate acyl azide, prepared by reaction of a carboxylic acid, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, with diphenylphosphoryl azide in the presence of an acid scavenger such as triethyl amine (Shioiri, T. et al., J. Amer. Chem. Soc. (1972), 94, 6203-5).
Alternatively, the intermediate of formula VIII, where R16 is the 4-formyl-dimethyl acetal moiety can be converted to ureas of formula VII via the urea forming reactions presented above. Deprotection of the of the intermediate [1-(4-substituted ureido-benzenesulfonyl)-piperidin-4-yl]-carboxaldehyde dimethyl acetal is carried out with formic acid or TFA as described above to give compounds of formula VII.
Compounds of formula III and formula VI where Z=SO2 and R1=amide analogs of the type IX 
where R12=alkyl, arylalkyl, heteroaryl, can also be prepared from the reaction of the intermediates of VII with an acid chloride prepared from a carboxylic acid, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the preparation of activated esters commonly used in peptide synthesis (see M. Bodanszky and A. Bodansky xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d, Springer-Verlag Berlin Heidelberg New York Tokyo, 1984)and known to those skilled in the art. Following deprotection or reduction as previously described provides compounds of the formula IX.
Compounds of formula VII can be prepared as outlined in scheme 2, scheme 3 or scheme 4 by reaction of 4-nitrobenzene sulfonyl chloride with either isonipecotamide or (piperidin-4-ylmethyl)-carbamic acid t-butyl ester or 4-formylpiperidine dimethyl acetal in methylene chloride or THF in the presence of a suitable acid scavenger such as diisopropyl amine. The nitro can be reduced to the amine by hydrogenation at atmospheric pressure in ethanol over 10% palladium on carbon or by a variety of other methods known to those skilled in the art.
Alternatively, the compound of formula VII where R16=Boc-aminomethyl, can be prepared from 4-aminomethylpiperidine according to the procedure outlined by J. D. Prugh et. al. Synth Comm, 22, 2357 (1992). A solution of benzaldehyde and 4-aminomethylpiperidine in toluene is heated at reflux until 1 equivalent of water was collected in a Dean-Stark trap. To the cooled reaction mixture is added 4-nitro-benzenesulfonyl chloride and a suitable acid scavenger such as diisopropylethyl amine. The intermediate coupled imine is decomposed by the addition of mild inorganic acid such as dilute HCl. Protection of the amine can be accomplished by treatment with ditertbutyldicarbonate in a suitable solvent system such as THF or dioxane-water.
Compounds of formula III and formula VI where Z=SO2, R1=compounds of the formula 
and R9 is heteroaryl, can be prepared from the intermediates of formula XI 
For compounds of formula XI where R17 is the methyl-carbamic acid t-butyl ester moiety or dimethyl acetal and R18 is F, an anion of a heterocycle is coupled with an arylfluoro compound as described by Caubere, P. et al., Bull. Soc. Chim. Fr. (1969), Issue 8, 2854-63. Thus a solution of [1-(4-fluorobenzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester or [1-(4-fluorobenzenesulfonyl)-piperidin-4-yl]-carboxaldehyde dimethyl acetal with an anion derived from potassium hydride of a nitrogen containing heterocycle, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in a suitable solvent such as DMF is maintained at 80xc2x0 C. to 100xc2x0 C. for at least 18 hours, followed by deprotection of the Boc or acetal groups as described above to give compounds of formula X.
For compounds of formula XI where R17 is the methyl-carbamic acid t-butyl ester moiety or dimethyl acetal and R18 is CN, oxadiazoles of formula X can be prepared by a method descibed by Hussein A. Q., Heterocycles, (1987), 26, 163. Thus the cyano is functionalized by reaction with ammonium hydroxide hydrochloride in the presence of potassium carbonate in a suitable solvent such as ethanol to give the intermediate amino(hydroxyimino)methyl compound. The intermediate is coupled with acid chlorides either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, in the presence of a suitable base such as pyridine followed by deprotection of the Boc or acetal groups as described above to give compounds of formula X where R9=5-substituted oxadiazoles.
Compounds of formula XI where R17 is the methyl-carbamic acid t-butyl ester moiety or dimethyl acetal and R18=heterocycles such as imidazol-2-ones can also prepared by the method described by Poindexter et al., JOC, (1992), 57, 6257. Thus, heating a mixture of aniline hydrochloride and a 2-substituted oxazolidinone at temperatures of at least 180xc2x0 C. for a period of at least 2 hours affords the intermediate phenylethylene diamine. The imidazolone is formed by reaction of this intermediate with triphosgene in the presence of a suitable base such as triethyl amine to give the intermediate 1-phenyl-3-substituted-imidazol-2-one. Sulfochlorination with chlorosulfonic acid provides the intermediate 4-(3-substituted-2-oxo-imidazolidin-1-yl)-benzenesulfonyl chloride which can be converted to compounds of formula XI by reaction with either piperidin-4-ylmethyl-carbamic acid t-butyl ester or 4-formylpiperidine dimethyl acetal using methodology described previously.
The intermediates of formula XI are prepared by coupling 4-fluorobenzensultonyl chloride with (piperidin-4-ylmethyl)-carbamic acid t-butyl ester or 4-formylpiperidine dimethyl acetal in DMF in the presence of a suitable acid scavenger such as such as potassium carbonate at 100xc2x0 C. for a period of at least 18 hours.
Compounds of formula III and formula VI where Z=bond, R1=compounds of the following type 
wherein B=CH or N and R19=NHR12, NHCH(COOR8)R12 or NHCH(COOH)R12 can be prepared via intermediate XIII: 
by standard peptide coupling reactions such as coupling an amine or amino acid ester, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, with an activated ester of VII prepared from benzyltriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate and an organic base like triethyl amine in a solvent such as DMF. Alternatively an activated ester of XIII may be prepared with 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide HCl and 1-hydroxybenzotriazole in the presence of an organic base such as N-ethyl morpholine in a solvent such as THF.
Compounds of formula V can be prepared via mono-chlorination of intermediates of the formula XIV 
wherein R is defined as in formula I by a procedure outlined by Kajigaeshi et al, Synthesis (1988), 546. Thus the appropriate acetyl compound, either available commercially or is known in the art, or can be prepared by procedures analogous to those in the literature for the known compounds, is treated with benzyltrimethylammonium tetrachloroiodate in a solution of methylene chloride to give a high yield of the mono-chloro product which can be purified by crystallization.
The mono-chloro product is chirally reduced to the intermediate XV 
with borane-THF and a chiral auxilary agent such as (R)-tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo[1,2-c][1,3,2]oxazaborole as described by Corey, E. J. et al., J. Org. Chem, (1991), 56, 442.
Subsequent reaction of the intermediate XI with sodium azide and an excess of sodium iodide in dimethylsulfoxide (DMSO) at 40xc2x0 C. to 60xc2x0 C. for 24 to 168 hours followed by reduction of the intermediate azide with hydrogen at 45 PSI over 10% palladium on carbon provides the compounds of formula VIII.
Alternatively, compounds of formula I where Z=SO2 can be prepared in simultaneous fashion using a technique known as xe2x80x9csolution phase parallel synthesisxe2x80x9d as described by Balkenhohl in Angew. Chem. Int. Ed. Engl., 1996, 35, 2288-2337. In this procedure two or more reaction products are simultaneously prepared in separate vessels. The number of reaction vessels being equal to the number of expected products. The ease of solution phase parallel synthesis is aided through the addition of xe2x80x9cresin bound reagentsxe2x80x9d to the reaction mixture which can be filtered through glass or polypropylene frits or other filtration methods known to those skilled in the art. Resin bound reagents are chemicals that are attached to polymeric materials, such as polystyrene, typically through covalent or ionic chemical bonds, and can assist in the reaction process itself or scavenge side products/excess starting materials from a reaction mixture. At the conclusion of the reaction the resin bound reagents are filtered from the reaction medium to provide a highly purified product which may now be obtained through solvent evaporation of the filtrate. 
According to the description above compounds of formula I where Z=SO2 can be prepared from resin bound imines of formula XVI by suspending the resin in a suitable, anhydrous solvent mixture such as 50:50 methanol-trimethylorthoformate (TMOF), distributing the resin suspension to separate vessels, adding a different amine of type V as the limiting reagent and resin bound reducing agent, such as borohydride on resin, to each vessel. The mixtures can be shaken 1-48 hours and then filtered. The filtrate can then be evaporated to obtain products. 
Resin bound imines of the type XVI can be prepared as described by Look in Tetrahedron Lett., 1995, 36, 2937-2940 by suspending a resin bound primary amine, either commercially available or available through literature procedures, treating the suspension with an aldehyde of the type XVII and removal of water by physical or chemical means. Typically, water is removed by chemical means through the use of trimethylorthoformate as the primary solvent. After 1-48 hours of agitation the suspension is filtered to obtain the resin bound imine as the residue. The filtration step also removes unreactive impurities in the aldehyde from the product resin. For example, a mixture of an aldehyde and an alcohol are reacted with aminomethyl resin and filtered. The filtrate contains alcohol impurity only while none of the impurity resides on the resin. 
Aldehydes of the type XVII are prepared by oxidation of corresponding sulfonamide alcohols of the type XVIII. In particular the alcohols are oxidized with resin bound chromium trioxide in 1,2-dichloroethane according to the method of Cainelli as described in J. Am. Chem. Soc., 1976, 98, 6737-6738. Filtration of the reaction suspension and evaporation of the solvent leads to the isolation of aldehydes XVII contaminated with up to 25% of the starting sulfonamide alcohol XVIII. 
Sulfonamide alcohols of the type XVIII can be prepared according to the procedure of Flynn as described in J. Am. Chem. Soc., 1997, 119, 4874-4881 by reacting an excess of the sulfonyl chloride (table 1 or 2) with 4-(hydroxymethyl)piperidine XIX in an appropriate solvent such as dichloromethane. Addition of an insoluble resin bound tertiary amine such as morpholinomethylpolystyrene reacts with and retains hydrogen chloride byproduct on the insoluble resin. After an appropriate reaction time of 1-48 hours a primary or secondary amine resin such as aminomethylpolystyrene can be added to react with the excess sulfonyl chloride which will retain the excess starting material on the insoluble resin. Filtration of the resulting suspension and evaporation of the solvent provides pure product that is free of byproducts and unreacted starting materials.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was confirmed with representative compounds of this invention in the following standard pharmacological test procedures, which measured the binding selectivity to the xcex21, xcex22, and xcex23 adrenergic receptors. Binding to the receptors was measured in Chinese Hamster ovary (CHO) cells that were transfected with adrenergic receptors. The following briefly summarizes the procedures used and results obtained.
Transfection of CHO cells with xcex21 and xcex22 adrenergic receptors: CHO cells were transfected with human xcex21- or xcex22-adrenergic receptors as described in Tate, K. M., Eur. J. Biochem., 196:357-361(1991).
Cloning of Human xcex23-AR Genomic DNA: cDNA was constructed by ligating four polymerase chain reaction (PCR) products using the following primers: an ATG-NarI fragment, sense primer 5xe2x80x2-CTTCCCTACCGCCCCACGCGCGATC3xe2x80x2 and anti-sense primer 5xe2x80x2 CTGGCGCCCAACGGCCAGTGGCCAGTC3xe2x80x2; a NarI-AccI fragment, 5xe2x80x2 TTGGCGCTGATGGCCACTGGCCGTTTG3xe2x80x2 as sense and 5xe2x80x2 GCGCGTAGACGAAGAGCATCACGAG3xe2x80x2 as anti-sense primer; an AccIi-StyI fragment, sense primer 5xe2x80x2 CTCGTGATGCTCTTCGTCTCACGCGC3xe2x80x2 and anti-sense primer 5xe2x80x2 GTGAAGGTGCCCATGATGAGACCCAAGG3xe2x80x2 and a StyI-TAG fragment, with sense primer 5xe2x80x2 CCCTGTGCACCTTGGGTCTCATCATGG3xe2x80x2 and anti-sense primer 5xe2x80x2 CCTCTGCCCCGGTTACCTACCC3xe2x80x2. The corresponding primer sequences are described in Mantzoros, C. S., et.al, Diabetes 45: 909-914 (1996). The four fragments are ligated into a pUC 18 plasmid (Gibco-BRL) and sequenced. Full length xcex23 AR clones (402 amino acids) containing the last 6 amino acids of hxcex23xe2x80x94AR are prepared with the xcex23-xcex2ARpcDNA3 from ATTC.
Binding Procedure: Clones expressing receptor levels of 70 to 110 fmoles/mg protein were used in the test procedures. CHO cells were grown in 24-well tissue culture plates in Dulbecco""s Modified Eagle Media with 10% fetal bovine serum, MEM non-essential amino acids, Penicillin-Streptompycin and Geneticin. On the day of test procedure, growth medium was replaced with preincubation media (Dulbecco""s Modified Eagle Media and incubated for 30 minutes at 37xc2x0 C. Preincubation medium was replaced with 0.2 ml treatment medium containing DMEM media containing 250 xcexcM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test compound dissolved in DMSO. Test compounds were tested over a concentration range of 10xe2x88x929 M to 10xe2x88x925 M for xcex23 cells and 10xe2x88x928 to 10xe2x88x924 M for xcex21 and xcex22 cells. Isoproterenol (10xe2x88x925 M) was used as an internal standard for comparison of activity. Cells were incubated at 37xc2x0 C. on a rocker for 30 min with the xcex23 cells and 15 min for xcex21 and xcex22 cells. Incubation was stopped with the addition of 0.2N HCl and neutralized with 2.5N NaOH. The plates, containing the cells and neutralized media, were stored at xe2x88x9220 degrees celsius until ready to test for cAMP using the SPA test kit (Amersham).
Data Analysis and Results: Data collected from the SPA test procedure were analyzed as per cent of the maximal isoproterenol response at 10xe2x88x925 M. Activity curves were plotted using the SAS statistical and graphics software. EC50 values were generated for each compound and the maximal response (IA) developed for each compound is compared to the maximal response of isoproternol at 10xe2x88x925 M from the following formula:   IA  =            %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      compound              %      ⁢              xe2x80x83            ⁢      activity      ⁢              xe2x80x83            ⁢      isoproterenol      
Table I shows the xcex23-adronergic receptor EC50 and IA values for the representative compounds of this invention that were evaluated in this standard pharmacological test procedure. These results show that compounds of the present invention have activity at the xcex23-adrenergic receptor. The compounds of this inventon had weaker or no activity at xcex21 and/or xcex22-adrenergic receptor.
Evaluation in xcex23 Knockout(KO) and xcex23 Transgenic(Tg) Mice: The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was also confirmed with representative compounds of this invention in an in vivo standard pharmacological test procedure which compared thermogenesis in transgenic mice (Tg mice) and xcex23-knockout mice (KO mice). The procedure used and results obtained are provided below.
xcex23-Adrenergic receptor knockout mice and xcex23 human transgenic mice are created on an inbred FVB background (Susulic, V. S., et.al., J. Biol. Chem., 1995, 270 (49), 29483-29492). Female FVB xcex23 transgenic and xcex23 knockout mice were used to determine in vivo activity and selectivity of xcex23 agonists. Compounds selected for in vivo testing had xcex23 EC50 less than 30 nm and were full agonists in CHO cells expressing human xcex23 receptors. These compounds were also selective in being 100-fold less responsive and partial agonists when tested in xcex21 and xcex22 transfected CHO cells. Compounds were tested for increased thermogenesis using the Oxymax indirect calorimeter (Columbus Instruments, Columbus, Ohio). Fed animals were placed in chambers for 3 hours to obtain baseline O2 and CO2 values. Eight fed mice were weighed in pairs and placed in 4 chambers, two per chamber. The relative gas content of each chamber was sampled and recorded at 10 to 12 minute intervals. For each sample, energy expenditure values were calculated by the Oxymax and expressed as kcal/hr. After 3 hours of baseline measurement, the mice were removed, treated and replaced in the chambers. The xcex23 agonists were injected at doses between 0.1 and 20 mg/kg i.p. and between 1.0 and 30 mg/kg for oral administration. Compounds in 10 mM or 10 mg/ml DMSO solutions were suspended in 0.5% methylcellulose: 0.1% tween-80 and injected i.p. or administered by oral gavage. Some compounds were suspended in 5.0% tween-80 for oral administration. Post-treatment kcal/hr values were taken between 40 minutes and 2.5 hours later. The 6 to 10 sample sections of the pre-treatment and post-treatment periods, which appear to best represent stable resting thermogenesis, were selected. Each of these sample values was corrected for body weight and used such that each pair of mice serves as its own baseline for both T test and percent increase in thermogenesis calculations. An ANOVA and a one sided T test (H1: Post greater than Pre) are performed using the SAS software modified to down weight extreme values. In a separate set of calculations, values that appear to be too high to represent resting thermogenesis are discarded (activity monitor sampling associated spikes in thermogenesis with ambulatory activity). The mean baseline value for each chamber is subtracted from mean post-treatment value for that chamber. This baseline-subtracted value is divided by the mean baseline value and multiplied by 100 to obtain a percent increase in thermogenesis for each chamber. The combined mean percent increase, standard deviation, and standard error of the mean for each chamber is calculated. Compounds were considered active if they were able to produce a statistically significant 15% increase in thermogenesis in xcex23 transgenic mice and no significant increase in xcex23 knockout mice. The results are shown in the table below.
Based on the results obtained id these standard pharmacological test procedures, representative compounds of this invention have been shown to be selective xcex23 adrenergic receptor agonists and are therefore useful in treating metabolic disorders related to insulin, resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
As used in accordance with this invention, the term providing an effective amount means either directly administering such a compound of this invention, or administering a prodrug, derivative, or analog which will form an effective amount of the compound of this invention within the body.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of this invention are administered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body. For the poultry and swine raisers, using the method of the present invention yields leaner animals.
Additionally, the compounds of this invention are useful in increasing the lean mass to fat ratio in domestic pets, for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.